1. We have validated a method for the continuous display and ‘on-line’ measurement of total pulmonary resistance in man, using a hybrid digital/analog computer. 2. The basic variables, which are measured by standard techniques, are flow rate of the mouth (V̇) and oesophageal pressure ( P oes ), and these are the only analog inputs necessary to the computer. 3. Resistance ( R L, cont ) is calculated continuously as: R L, cont = ( P oes - V/C )/V̇ where V is tidal volume and C is the dynamic compliance. R L, cont is continuously displayed as an analog signal on an oscilloscope. 4. Changes in resistance, measured by this method over a wide range of values in three subjects, showed an almost exact correlation with those measured by a standard method (Mead-Whittenberger).

1. The cardiovascular effects of intravenous injections of interleukin-1 (IL-1) and tumour necrosis factor (TNF) have been investigated in the conscious rabbit. They have been compared with the effects of bacterial lipopolysaccharide (LPS) because both IL-1 and TNF are released from macrophages by LPS. 2. IL-1, TNF and Escherichia coli J5-LPS all caused hypotension when given intravenously in a dose with low mortality. The time course of the hypotension caused by IL-1 and LPS was similar, although the maximal fall in mean blood pressure occurred earlier after IL-1. TNF produced a more sustained fall in blood pressure. Hypotension was not accompanied by a compensatory tachycardia after any of the test substances. Hypotension was associated with a fever after TNF, hypothermia after LPS and no significant change in temperature after IL-1. 3. The packed cell volume did not change during hypotension in any of the study groups, implying that the hypotension was not due to fluid loss resulting from increased capillary permeability. 4. IL-1 and TNF are candidates for the role of effectors of LPS-induced hypotension.

1. The subjective changes accompanying alterations in inspired oxygen concentration during heavy exercise have been investigated single blind, in normal subjects. 2. In particular, the intensity of the sensation of breathlessness was quantified using a visual analogue scale and changes were compared with those in objective ventilatory measures. 3. Eleven subjects performed three steady-state workload exercise tests on different days and 100% O 2 , 15% O 2 or air were randomly administered for a fixed interval during each test. 4. Compared with air breathing, all subjects felt less breathless during 100% O 2 breathing, and ten of them felt more breathless when inspiring 15% O 2 ; these changes were reversed on return to air breathing. 5. During and after 100% O 2 , the time course of changes in breathlessness was similar to those for ear arterial oxygen saturation and minute ventilation such that it could be a secondary response to either. However, during and after inspiration of 15% O 2 , changes in breathlessness occurred relatively more quickly than those in ventilation, more closely reflecting changes in oxygen saturation; this suggests that hypoxia, per se , could contribute to the genesis of this sensation. 6. Individual variability in breathlessness responses to exercise and changes in inspired oxygen concentration did not correlate with objective ventilatory changes; neither were changes in breathlessness in the group particularly associated with changes in respiratory frequency or tidal volume.

1. The ventilatory response to maximal incremental exercise and the accompanying sensation of breathlessness were studied after the inhalation of 0.9% sodium chloride (saline) and 5% bupivacaine aerosols in six patients with interstitial lung disease. 2. The adequacy of airway anaesthesia induced by bupivacaine aerosol was confirmed by the absence of the cough reflex to 5% citric acid aerosol on completion of exercise. 3. All subjects first performed a trial exercise test to familiarize them with the procedure and to assess the degree of arterial oxygen desaturation on exercise. In subsequent tests, supplementary oxygen was given to maintain the saturation at 95% or above. 4. Airway anaesthesia had no effect on the ability to perform exercise as assessed by maximum workload, CO 2 production or heart rate. No significant changes were seen on the pattern of breathing, minute ventilation or endtidal P co 2 on exercise. There was, however, a small but statistically significant increase in ventilation related to CO 2 production ( V E / V co 2 ) at the end of exercise. 5. There was a tendency for breathlessness to be increased by airway anaesthesia but this did not reach statistical significance. 6. These results provide no evidence that vagal afferent activity is responsible for the abnormal ventilatory response to exercise in patients with interstitial lung disease. The perception of breathlessness in these patients was not diminished by anaesthesia of the airway.

1. Continuous recordings of arterial pH, ventilation, airway CO 2 and heart rate were made during rest and during 3–4 min periods of rhythmic leg exercise in four renal patients with arteriovenous shunts. 2. The patients were anaemic (haemoglobin 6.5–9.0 g/dl) but had a normal ventilatory response to exercise as judged by the ratio of the change in ventilation to the change in CO 2 production. 3. Breath-by-breath oscillations in arterial pH disappeared for the majority of the exercise period in each patient. 4. Changes in mean arterial pH and end-tidal CO 2 tension with exercise were inconsistent between subjects but consistent within a given subject. On average, mean arterial pH rose by 0.011 pH unit. Changes in end-tidal CO 2 tension reflected changes in mean pHa by falling on average by 1 mmHg (0.13 kPa). 5. Hypercapnia and acidaemia were not found to be necessary for the ventilatory response to moderate exercise.

1. The effect of adding low-level (2.7 cmH 2 O 1 −1 s) external respiratory resistive loads on exercise-induced breathlessness has been examined in naive normal subjects; the intensity of this loading was chosen to simulate that confronting an asthmatic subject during exercise. 2. Each of 18 subjects performed two separate tests in which workload was oscillated while the respiratory loading was changed every minute between no loading, inspiratory loading only, and inspiratory plus expiratory loading. Each loading condition was given three times, and both these changes and those in workload were unpredictable as far as the subject was concerned. 3. The purpose was to ‘confuse’ subjects and obtain subjective estimates of their intensity of breathlessness independent of any expectation associated solely with the readily perceptible changes in external resistances to breathing. The study design was balanced for the group as a whole, both in terms of workload and respiratory loading condition. 4. The addition of these respiratory resistive loads during exercise did not result in a significant increase in the intensity of breathlessness. 5. Estimates of the rate of work of breathing revealed that this increased more with respiratory loading than it did as ventilation rose throughout the test; on the other hand, the intensity of breathlessness increased by a greater extent with continued exercise compared with the changes accompanying the addition of respiratory loads. 6. It is concluded that the intensity of the sensation of breathlessness experienced by normal subjects during exercise is not simply a reflection of an increased rate of work of breathing being performed by the respiratory muscles. 7. It is further suggested that similar studies in which internal resistances are increased experimentally are indicated in order to analyse the factors underlying the breathlessness of asthma.

1. Nine normal subjects performed 6 min, constant-workload, exercise tests on a bicycle ergometer at either a ‘high workload’ or at a ‘low workload’. During the first ‘high workload’ test their spontaneous breathing pattern was recorded on to magnetic tape. During one subsequent ‘high workload’ test and one ‘low workload’ test they voluntarily copied their recorded breathing pattern. During a second ‘low workload’ test they breathed spontaneously. Isocapnia was maintained by the operator throughout both the copying tests. During the exercise tests ventilation was recorded and subjects indicated the level of their sensation of breathlessness every 30 s. 2. Subjects felt markedly less breathless when a proportion of their ventilation was produced by voluntary effort than when the same total level of ventilation was produced entirely by the stimulus of exercise. Furthermore, voluntary isocapnic hyperventilation during exercise did not increase breathlessness above that normally associated with that level of exercise. 3. These results suggest that it is reflexly driven ventilation, and not simply the level of ventilation itself, which relates to the level of breathlessness during exercise.

1. Six patients with chronic airflow limitation rebreathed CO 2 . Subsequently they voluntarily copied their stimulated breathing pattern while normocapnia was maintained. On a separate occasion four of these patients performed progressively increasing exercise and later copied these breathing patterns. 2. During all experiments flow, ventilation and pleural pressures were recorded. In addition, breathlessness was measured on a visual analogue scale every 30 s. 3. In these patients voluntary copying of either form of stimulated breathing resulted in diminished breathlessness and in some cases in complete abolition of the sensation, despite similar levels and patterns of ventilation in the two situations. 4. No systematic or consistent differences in the mechanics of breathing between stimulated and voluntarily copied breathing were found. 5. There was no correlation found between breathlessness score and any mechanical variable measured. 6. These results show that despite similarity in mechanics between stimulated and voluntary hyperventilation, the sensation of breathlessness is much diminished during the latter in these patients. This suggests that the sensation of breathlessness is more dependent upon the awareness of central processing than upon input from peripheral mechanoreceptors.

1. Nine patients with chronic obstructive airways disease performed a 6 min self-paced walk (breathing air) on a treadmill and then identical (but operator-controlled) treadmill walks breathing either air or supplemental oxygen sufficient to just prevent arterial oxygen desaturation during the exercise. 2. During the exercises, ventilation was recorded and patients recorded their sensation of breathlessness on a visual analogue scale (VAS) every 30 s. 3. Breathing supplemental oxygen produced a small fall in mean exercise ventilation and a large and consistent reduction in mean exercise breathlessness. In seven patients the VAS scores were higher on air than with supplemental oxygen, at similar levels of ventilation. An analysis of co-variance, to control for reduction in ventilation, showed a decrease in mean breathlessness when breathing supplemental oxygen, significant at the 8% level. 4. The reduction in breathlessness produced by preventing exercise desaturation cannot be explained by the decrease in ventilation. This suggests that hypoxia may be a stimulus for breathlessness. The mechanism is unknown.

1. The respiratory and cardiovascular effects of capsaicin injection into the superior vena cava and an arm vein were studied in three normal subjects. 2. No changes were seen in tidal volume, inspiratory time or expiratory time after capsaicin injection. Instantaneous heart rate, systolic blood pressure and diastolic blood pressure remained unchanged. 3. Central and peripheral intravenous injections of capsaicin but not control solution above a threshold of 0.5 μg/kg produced dose-dependent sensations sequentially in the chest, face, rectum and extremities. The chest sensation, a ‘raw, burning’ feeling, occurred 3–4 s after central capsaicin injection. No subject reported feeling breathless. In one subject the maximum tolerable dose of capsaicin (4 μg/kg) produced paroxysmal coughing 3.9 s after a central injection. 4. In two of the subjects capsaicin injection was repeated after inhalation of a 5% bupivacaine aerosol (aerodynamic mass median diameter 4.8, μm), sufficient to block the cough reflex to a 5% citric acid aerosol. Prior inhalation of local anaesthetic aerosol abolished the chest sensation after capsaicin injection; the other sensations were unaffected. 5. This study demonstrates that stimulation of receptors accessible from the pulmonary vascular bed does not evoke the pulmonary chemoreflex in conscious man but can produce coughing. It provides evidence for the existence of a nociceptive system of nerve endings in the lung parenchyma that can be blocked by inhaled local anaesthetic aerosol.

1. Normal subjects show wide variability in their sensory scaling of breathlessness for equivalent degrees of ventilatory stimulation and behave ‘characteristically’ irrespective of stimulus type. 2. Observed differences are not explained by physical characteristics, ventilatory sensitivity or pattern of breathing although there is a weak association with the degree of physical fitness. 3. Differences are seen when scaling is performed with reference to both rigidly defined extremes of breathlessness (visual analogue scaling) and a subject's own relative changes in the intensity of this sensation (magnitude estimation). 4. These findings may explain the common observation, in patients with respiratory disease, of dyspnoea out of proportion to the pathophysiological state.

1. This study investigates the mechanisms underlying the perception of breathlessness induced by hypoxia and hypercapnia in both naive normal subjects and patients with respiratory mechanical problems. 2. In normal subjects separately receiving both oscillating hypercapnic and hypoxic ventilatory stimulation, equivalent peak stimulus intensities in end-tidal gas were associated with a ‘damped’ ventilatory response when the frequency of stimulation was increased. A concomitant fall in peak breathlessness levels on a visual analogue scale was recorded in each case. 3. In normal subjects and patients, the voluntary copying of a ventilatory pattern recorded during oscillating hypercapnic stimulation was associated with a marked diminution or complete absence of breathlessness despite equivalent levels of peak ventilations achieved. 4. Voluntary copying of hypercapnic stimulated ventilation was not associated with any demonstrable change in the distribution of muscle movements between the chest wall and abdomen. 5. These results suggest that the intensity of breathlessness depends on the level of effective reflex stimulation of the respiratory-related neurones in the medulla. They cannot be explained solely in terms of perception of afferent neural information arising from either chemoreceptors or respiratory mechanoreceptors.

1. The intensity of breathlessness induced by ventilatory stimulation resulting from hypercapnia, hypoxia or exercise has been quantified in normals by using the two different sensory scaling techniques of linear visual analogue scaling and ratio magnitude estimation. 2. In naive individuals both techniques show good face validity. 3. When related to ventilation, quantification of breathlessness is moderately reproducible with both methods, even when subjects are kept in ignorance of the pattern of ventilatory stimulation. 4. There is a small within- and large between-subject variability with both scaling techniques; possible factors responsible are discussed. 5. The reproducibility of visual analogue scaling when related to ventilation is independent of the nature of the ventilatory stimulus and is maintained over intervals as long as 1 week when memory for the score given is unlikely to be an important factor. 6. The difficulties of interpreting subjective estimates of perceived breathlessness are discussed, together with the relative merits of the two scaling techniques.

1. Unrestrained proteolysis in the lung is believed to initiate emphysema, a disease common among tobacco smokers. However, few studies have found extracellular protease activity in human lung lavage. 2. In this investigation, elastase and serine protease activities were measured in broncho-alveolar lavage supernatants (BAL) from patients undergoing routine investigations. Significantly more elastolytic activity (against insoluble [ 3 H]-elastin) was recovered in the lavage of smokers than that of non-smokers. However, no significant difference was found when the levels of serine proteolytic activity (against N -succinyl-L-trialanyl- p -nitroanilide) were compared. 3. The elastolytic component of the protease activity rose from 5% in non-smokers’ BAL to over 30% in that of smokers, suggesting that elastase activity is selectively enhanced by smoking. In lavages from most smokers, 80% or more of the elastase activity was serine-dependent, whereas lavages from non-smokers contained variable proportions of serine elastase. 4. Both α 1 -proteinase inhibitor (α 1 -PI) and a low molecular weight antiprotease, bronchial mucus proteinase inhibitor (BMPI) were detectable in the lavage samples, the latter contributing up to 76% of the total antiprotease quantified in the lavage. Functional antiprotease was detected in 85% of the lavages. 5. Since there were no differences in either antiprotease levels or functional inhibitory capacities between lavages from smokers and controls, it is concluded that the imbalance in the protease/antiprotease profile of the smokers’ lung results from an enhancement of proteases, specifically of elastolytic activity, rather than a reduction in inhibitory capacity.

1. Nine men with severe chronic obstructive airways disease (COAD), known to desaturate on exercise, performed a 6 min self-paced walk on a treadmill, followed by a bicycle exercise with workloads adjusted to mimic the oxygen consumption achieved on the treadmill. During both exercises, ventilation, oxygen consumption, carbon dioxide production, P a o 2 , P a co 2 , pH and arterial lactate were measured and subjective breathlessness recorded. 2. A reasonable match of oxygen consumption between the two exercises was achieved. In all subjects P a o 2 fell to a lower level during treadmill compared with bicycle exercise. Ventilation, carbon dioxide production and arterial lactate were higher during bicycle exercise. Subjective breathlessness was greater during bicycle exercise, in proportion to the higher ventilation on the bicycle. 3. The greater anaerobiosis occurring on the bicycle led to acidosis and an increased ventilation, minimizing the exercise fall in P a o 2 . 4. Bicycle testing may seriously underestimate exercise desaturation occurring during level walking in patients with severe COAD.

1. The effect on ventilation of airway anaesthesia, produced by the inhalation of a 5% bupivacaine aerosol (aerodynamic mass median diameter = 4.77 μm), was studied in 12 normal subjects. 2. The dose and distribution of the aerosol were determined from lung scans after the addition to bupivacaine of 99m Tc. Bupivacaine labelled in this way was deposited primarily in the central airways. The effectiveness and duration of airway anaesthesia were assessed by the absence of the cough reflex to the inhalation of three breaths of a 5% citric acid aerosol. Airway anaesthesia always lasted more than 20 min. 3. Resting ventilation was measured, by respiratory inductance plethysmography, before and after inhalation of saline and bupivacaine aerosols. The ventilatory response to maximal incremental exercise and, separately, to CO 2 inhalation was studied after the inhalation of saline and bupivacaine aerosols. Breathlessness was quantified by using a visual analogue scale (VAS) during a study and by questioning on its completion. 4. At rest, airway anaesthesia had no effect on mean tidal volume ( V T ), inspiratory time ( T i ), expiratory time ( T e ) or end-tidal P co 2 , although the variability of tidal volume was increased. On exercise, slower deeper breathing was produced and breathlessness was reduced. The ventilatory response to CO 2 was increased. 5. The results suggest that stretch receptors in the airways modulate the pattern of breathing in normal man when ventilation is stimulated by exercise; their activation may also be involved in the genesis of the associated breathlessness. 6. A hypothesis in terms of a differential airway/alveolar receptor block, is proposed to explain the exaggerated ventilatory response to CO 2 .